During the past decade we developed and studied a model of autoimmune renal tubulointerstitial disease (RTD) in guinea pigs which led directly to the discovery of a similar, previously unrecognized form of renal disease in man. Our work delineated several crucial factors in the pathogenesis. RTD is induced by autoantibodies reacting with renal tubular basement membrane (TBM); damage to renal tubules and TBM is associated with activation of the alternative complement pathway and infiltration of the target tissues by lymphocytes and macrophages. This model of RTD in guinea pigs is being extended to inbred mice in order to study certain basic genetic aspects of autoimmunity which cannot be explored in guinea pigs. Experiments dealing with mechanisms of self-recognition and loss of tolerance to self-renal antigens will be investigated in this genetically and immunobiologically well-defined species. Working progress shows that loss of self-tolerance to TBM can occur spontaneously in some (NZB x NZW)F1 mice with lupus nephritis. Experimentally, RTD was induced by immunization with cross-reacting rabbit TBM. Studies in inbred H-2 congenic and recombinant mice indicate that genetic traits associated with the major histocompatibility complex (H-2) govern susceptibility and resistance. Since there is a long delay between autoantibody deposition on TBM and onset of RTD, we suspect that a cell-mediated autoimmune mechanism may also be involved in RTD in mice. Thus, the differences and similarities of pathogenetic mechanisms of RTD in mice and guinea pigs will be examined further to determine the genetic traits which influence susceptibility to RTD and mechanisms which produce the renal pathology.